Crystal structure of a dimeric Ser49- PLA₂-like myotoxic component of the Vipera ammodytes meridionalis venomics reveals determinants of myotoxicity and membrane damaging activity

TY - JOUR

T1 - Crystal structure of a dimeric Ser49- PLA₂-like myotoxic component of the Vipera ammodytes meridionalis venomics reveals determinants of myotoxicity and membrane damaging activity

AU - Georgieva, Dessislava

AU - Coronado, Monika

AU - Oberthür, Dominik

AU - Buck, Friedrich

AU - Duhalov, Deyan

AU - Arni, Raghuvir K

AU - Betzel, Christian

PY - 2012/4/1

Y1 - 2012/4/1

N2 - Myotoxicity and membrane damage play a central role in the life-threatening effects of the viper envenomation. Myotoxins are an important part of the viper venomics. A Ser49 PLA₂-like myotoxin from the venom of Vipera ammodytes meridionalis, the most venomous snake in Europe, was crystallized and its three-dimensional structure determined. The toxin is devoid of phospholipolytic activity. The structure demonstrates a formation of dimers. In the dimers functionally important peptide segments, located on the protein surface, point in the same direction which can strengthen the pharmacological effect. This supports the hypothesis about the physiological importance of the toxin oligomerization for the myotoxicity and membrane damage. The crystallographic model revealed that the structural determinants of myotoxicity (a positively charged C-terminal region and a hydrophobic knuckle) are fully exposed on the protein surface and accessible for interactions with target membranes. Distortion of the catalytic site region explains the absence of enzymatic activity. The structure reveals anion-binding sites which can be considered as possible sites of interactions of the toxin with a negatively charged membrane surface. The high structural similarity of the Ser49 myotoxin and Asp49 PLA₂ from the same venom suggests an evolutionary relationship: probably, the Ser49 myotoxin is a product of evolution of the catalytically active phospholipase A₂. The first toxin lost the enzymatic activity which is not necessary for the myotoxicity but preserved the cytotoxicity and membrane damaging activity as important components of the venom toxicity.

AB - Myotoxicity and membrane damage play a central role in the life-threatening effects of the viper envenomation. Myotoxins are an important part of the viper venomics. A Ser49 PLA₂-like myotoxin from the venom of Vipera ammodytes meridionalis, the most venomous snake in Europe, was crystallized and its three-dimensional structure determined. The toxin is devoid of phospholipolytic activity. The structure demonstrates a formation of dimers. In the dimers functionally important peptide segments, located on the protein surface, point in the same direction which can strengthen the pharmacological effect. This supports the hypothesis about the physiological importance of the toxin oligomerization for the myotoxicity and membrane damage. The crystallographic model revealed that the structural determinants of myotoxicity (a positively charged C-terminal region and a hydrophobic knuckle) are fully exposed on the protein surface and accessible for interactions with target membranes. Distortion of the catalytic site region explains the absence of enzymatic activity. The structure reveals anion-binding sites which can be considered as possible sites of interactions of the toxin with a negatively charged membrane surface. The high structural similarity of the Ser49 myotoxin and Asp49 PLA₂ from the same venom suggests an evolutionary relationship: probably, the Ser49 myotoxin is a product of evolution of the catalytically active phospholipase A₂. The first toxin lost the enzymatic activity which is not necessary for the myotoxicity but preserved the cytotoxicity and membrane damaging activity as important components of the venom toxicity.

KW - Amino Acid Sequence

KW - Animals

KW - Aspartic Acid

KW - Catalytic Domain

KW - Cell Membrane

KW - Crystallography, X-Ray

KW - Hydrogen Bonding

KW - Molecular Sequence Data

KW - Phospholipases A2

KW - Protein Multimerization

KW - Protein Structure, Secondary

KW - Proteomics

KW - Sequence Homology, Amino Acid

KW - Serine

KW - Viper Venoms

KW - Viperidae

U2 - 10.1039/c2mb05490f

DO - 10.1039/c2mb05490f

M3 - SCORING: Journal article

C2 - 22362132

VL - 8

SP - 1405

EP - 1411

JO - MOL BIOSYST

JF - MOL BIOSYST

SN - 1742-206X

IS - 5

ER -